Piper nigrum L. (Piperaceae)

Synonym(s) and related species

Black and white pepper are derived from the fruits of the same species, Piper nigrum L. Black pepper is the unripe fruit which has been immersed in hot water and dried in the sun, during which the outer pericarp shrinks and darkens into a thin, wrinkled black layer. White pepper consists of the seed only, prepared by soaking the fully ripe berries, removing the pericarp and drying the naked seed.

Long pepper, Piper longum L., is a closely related species where the fruits are smaller and occur embedded in flower ‘spikes’, which form the seed heads.

Constituents

Alkaloids and alkylamides, the most important being piperine, with piperanine, piperettine, piperlongumine, pipernonaline, lignans and minor constituents such as the piperoleins, have been isolated from the fruits of both species of pepper. Black pepper and long pepper also contain a volatile oil which may differ in constitution, but is composed of bisabolene, sabinene and many others; white pepper contains very little. The pungent taste of pepper is principally due to piperine, which acts at the vanilloid receptor.

Use and indications

Pepper is one of the most popular spices in the world, and it is also used as a folk medicine in many countries. It is used as a stimulant and carminative, and is reputed to have anti-asthmatic, anti-oxidant, antimicrobial, hepatoprotective and hypocholesterolaemic effects. Most of the pharmacological effects reported to date are attributed to piperine. A black pepper extract containing 95% piperine is used in a number of herbal supplements.

Both long pepper and black pepper are important ingredients of many Ayurvedic herbal medicines where they are intended to enhance absorption of other medicines, for example in the traditional formula known as Trikatu, which contains Piper nigrum, Piper longum and Zingiber officinale (ginger) in a ratio of 1:1:1. There is increasing evidence to support this rationale as well as some of the other traditional uses, but it should be noted that the actions of Trikatu are not always the same as for pepper extracts or pure piperine, and Trikatu has been implicated in reducing rather than enhancing bioavailabihty of some drugs. Trikatu is also used as a digestive aid.

Pharmacokinetics

Pipeline, given to mice has been shown to delay gastrointestinal transit time in a dose-dependent manner. A non-significant trend towards a delay in gastrointestinal transit has also been seen in a study in 14 healthy fasting subjects given 1.5 g black pepper. This has been suggested as one way that piperine might increase the absorption of drugs, but its clinical significance is unclear, as pepper is normally ingested as part of a meal.

It has been known for some time that pepper, and piperine in particular, inhibit cytochrome P450, but it is only more recently that activity against specific human isoenzymes has been tested. Piperine has been found to inhibit the cytochrome P450 isoenzyme CYP3A4, see verapamil, in vitro. The bisalkaloids, dipiperamides D and E have also been shown in vitro to inhibit this isoenzyme using nifedipine as a probe substrate. Similarly, methanolic and ethanolic extracts of Piper nigrum fruit inhibited CYP3A4 and CYP2D6 in vitro using erythromycin and dextromethorphan as probe substrates, although only the activity of the methanolic extract against CYP3A4 had a low IC5o value. These findings have also been published elsewhere. Piperine did not alter CYP2C, see verapamil.

In vitro studies suggest that piperine may inhibit P-glycoprotein, see digoxin, and ciclosporin.

It has also been suggested, using data from in vitro studies using guinea-pig cell cultures, and in vivo studies in ratsthat piperine may inhibit glucuronidation via the UDP-glucuronyltransferase enzyme system, which is involved in the metabolism of a number of drugs.

Interactions overview

Pipeline, the active alkaloidal constituent of pepper, markedly increased the AUC of a single dose of nevirapine and of theophylline when given at a dose that might easily be achieved with pipeline-containing supplements. Some caution might be appropriate with these combinations. The AUC of a single dose of propranolol was similarly increased, but this is less likely to be clinically important. Increases in phenytoin levels have also been demonstrated, and high-dose piperine also increased the AUC of rifampicin.

Various animal studies have shown increased levels of amoxicillin, barbiturates, NSAIDs and oxytetracycline with piperine, but little effect on cefadroxil. Piperine also had an antithyroid effect in animals. In other animal studies, Trikatu decreased diclofenac and isoniazid levels.

Pepper + Barbiturates

The interaction between piperine and pentobarbital or phenobarbital is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a single-dose study in rats, pre-treatment with increasing doses of oral piperine from 10 to 50 mg/kg increased the pentobarbital sleeping time (up to twofold). Blood levels of pentobarbital were raised (by 38% at 45 minutes). Piperine at a lower dose of 5 mg/kg had no significant effect on the pentobarbital sleeping time. When the study was repeated after pre-treatment with phenobarbital 100 mg/kg for 7 days, the pentobarbital sleeping time was still prolonged after administration of piperine, but the length of sleeping time was much less than without barbiturate pretreatment.

Mechanism

It was suggested that the increase in sleeping time induced by pentobarbital and phenobarbital was a result of inhibition of drug metabolising enzymes by piperine.

Importance and management

This preclinical study provides some limited evidence that piperine, the main active constituent of pepper, might increase the effects of pentobarbital and possibly also phenobarbital. While it is not possible to directly apply these data to the clinical situation, it should be noted that the doses used are probably unlikely to be ingested from pepper itself, or from piperine-containing supplements.

The interaction or lack of interaction between piperine and amoxicillin, cefadroxil or cefotaxime is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

(a) Amoxicillin

In a single-dose study in rats, giving piperine 10 mg/kg or 20 mg/kg followed 30 minutes later by oral amoxicillin 100 mg/kg significantly increased the maximum amoxicillin plasma concentration by 90% and 124%, respectively, and the AUC by 66% and 107%, respectively. The time to reach maximum levels was reduced, and the half-life increased.

(b) Cefadroxil

In a single-dose study in rats, giving piperine 10 mg/kg or 20 mg/kg followed 30 minutes later by oral cefadroxil 100 mg/kg had no effect on the pharmacokinetics of cefadroxil.

(c) Cefotaxime

In a single-dose study in rats, giving piperine 10 mg/kg or 20 mg/kg followed 30 minutes later by intraperitoneal cefotaxime 10 mg/kg significantly increased the maximum cefotaxime plasma concentration by 51% and 71%, respectively, the AUC by 71% and 118%, respectively, and the half-life by 44% and 65%, respectively.

Mechanism

Unknown. The increase in elimination half-life of amoxicillin and cefotaxime suggests a mechanism affecting drug clearance, and not a mechanism of increased gastrointestinal absorption. Although the authors suggest that an effect on drug metabolising enzymes cannot be ruled out, this is unlikely as none of these antibacterials undergoes significant metabolism by this route.

Importance and management

This preclinical study provides some evidence that piperine, the main active constituent of pepper, might increase exposure to some antibacterials. While it is not possible to directly apply these data to the clinical situation, the level of increases seen would not be expected to be clinically important. It should be noted that the doses used are probably unlikely to be ingested from pepper itself, or from piperine-containing supplements

Pepper + Ciclosporin

The interaction between piperine and ciclosporin is based on experimental evidence only.

Evidence, mechanism, importance and management

In an in vitro study, the transport of ciclosporin by P-glycoprotein was modestly inhibited in the presence of piperine, in a concentration-dependent manner. It is difficult to apply the findings of one experimental study to human intake of pepper and a clinical study is needed to assess whether ingestion of pepper or piperine-containing supplements actually alters ciclosporin levels. Until more is known, bear this finding in mind in the event of unexpected outcomes in patients taking ciclosporin and piperine-containing supplements.

Pepper + Digoxin

The interaction between piperine and digoxin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence and mechanism

In two in vitro studies, piperine inhibited the transport of digoxin by P-glycoprotein in a concentration-dependent manner. In one of these studies, piperine 50 micromol had an effect comparable to verapamil 100 micromol, a known P-glycoprotein inhibitor.

Importance and management

Unclear. It is difficult to apply this finding to human intake of pepper. The authors of one of the studies suggest that an inhibitory concentration of piperine could potentially be achieved in vivo after ingestion of soup containing 1 g black pepper. This amount could have the effect of increasing plasma digoxin levels. However, a clinical study is needed to assess whether ingestion of pepper or piperine-containing supplements actually alters digoxin levels. Until more is known, bear this finding in mind in the event of unexpected outcomes in patients taking digoxin and piperine-containing supplements.

Pepper + Food

No interactions found between pepper and food. Note that pepper is an ingredient in many foods. For mention that piperine increased the absorption of one green tea catechin, see Tea + Herbal medicines.

Pepper + Herbal medicines; Coenzyme Q10

For a study showing that piperine modestly increased the AUC of one dose of coenzyme Q10, see Coenzyme Q10 + Herbal medicines; Pepper.

For mention that piperine increased the bioavailability of curcumin, see Turmeric + Herbal medicines; Pepper.

Pepper + Isoniazid

The interaction between piperine and isoniazid is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a single-dose study, rabbits were given isoniazid 14mg/kg alone or with Trikatu 500 mg, which contained 10 mg of the active principle piperine. Trikatu was found to significantly reduce the maximum plasma levels and AUC of isoniazid by 35% and 39%, respectively. Trikatu is an Ayurvedic medicine which contains ginger, black pepper and long pepper in a 1:1:1 ratio.

Mechanism

It has been suggested that Trikatu delays gastric motility, causing retention of the isoniazid in the stomach. Since isoniazid is largely absorbed from the intestine, this might explain the decrease in plasma isoniazid concentrations.

Importance and management

If the findings of the study in animals were also replicated in humans, it would seem possible that ingestion of Trikatu with isoniazid may reduce isoniazid levels to below the required minimum inhibitory concentration. However, the widespread use of pepper in cooking and lack of reports of treatment failure with isoniazid provide some reassurance that an interaction is unlikely. Nevertheless, bear in mind the possibility of an interaction if there is any indication of a lack of isoniazid efficacy in a patient taking Trikatu.

Pepper + Nevirapine

Piperine markedly increases the AUC of a single dose of nevirapine in healthy subjects.

Clinical evidence

In a well-controlled study in 8 healthy subjects who received piperine 20 mg daily for 7 days, with a single 200-mg dose of nevirapine at the same time as the piperine on day 7, the maximum plasma concentration and AUC of nevirapine were markedly increased by about twofold and 2.6-fold, respectively. The estimated elimination half-life of nevirapine was not significantly altered. In this single-dose study there was no difference in the incidence of adverse events.

Experimental evidence

No relevant data found.

Mechanism

Uncertain. It was suggested that piperine inhibited the cytochrome P450 isoenzyme CYP3A4, which is involved in the metabolism of nevirapine. However, since the elimination half-life of nevirapine was unaltered, it is unlikely that hepatic CYP3A4 was affected. Also, inhibition of gastrointestinal CYP3A4 would not explain the marked increase in nevirapine levels seen, because nevirapine is already over 90% bioavailable. On repeated dosing nevirapine induces its own metabolism (hence the need to increase the dose after 2 weeks), but in this study nevirapine was given as a single dose, so autoinduction would not have played any part. Subjects in this study were fasting, but food does not affect nevirapine pharmacokinetics.

Importance and management

This study appears to show that piperine markedly increases the exposure to single-dose nevirapine that might easily be achieved with piperine-containing supplements or even from consuming black pepper. However, at present there is no clear explanation for the finding, and further investigation is clearly warranted. Furthermore, how the findings relate to the use of multiple-dose nevirapine is unknown, especially as nevirapine induces its own metabolism. Although no adverse effects were seen in this small single-dose study in healthy subjects, nevirapine is known to cause a dose-related rash, and to be hepatotoxic. Until more is known, it would be prudent to be cautious with the use of piperine-containing supplements in patients taking nevirapine.

Pepper + NSAIDs

The interaction between piperine and diclofenac, indometacin and oxyphenbutazone is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

(a) Diclofenac

In a single-dose study in rabbits, the AUC of diclofenac 25 mg/kg was markedly reduced by about 80% when given with Trikatu 500 mg/kg. In this study, a suspension of a combination of diclofenac and Trikatu was used. The anti-inflammatory effects of diclofenac 25 mg/kg were also reduced by Trikatu 500 mg/kg when the combination was given to rats. Trikatu is an Ayurvedic medicine that contains ginger, black pepper and long pepper in a 1:1:1 ratio.

(b) Indometacin

In a single-dose study in rabbits, Trikatu 500 mg/kg modestly increased the maximum plasma levels of indometacin 7 mg/kg by 29%, without affecting the AUC or other pharmacokinetic parameters. Trikatu is an Ayurvedic medicine that contains ginger, black pepper and long pepper in a 1:1:1 ratio.

(c) Oxyphenbutazone

A single-dose study in rats and mice found that giving piperine 10 mg/kg at the same time as oxyphenbutazone 50 mg/kg modestly increased the AUC and maximum plasma levels of oxyphenbutazone by 28% and 36%, respectively. The anti-inflammatory activity of oxyphenbutazone in an animal model was increased.

Mechanism

Unknown. It was expected that Trikatu might increase the bioavailability of diclofenac and indometacin. It is possible that there was an incompatibility between diclofenac and a constituent of Trikatu in the single suspension that resulted in the decreased absorption. The increased bioavailability of oxyphenbutazone with piperine was attributed to increased gastric absorption and inhibition of hepatic metabolism of oxyphenbutazone.

Importance and management

The relevance of these disparate findings in animal studies to humans is unclear. Both ginger and pepper, which make up the Trikatu herbal formulation, are used extensively as food ingredients, and as there appear to be no reports of an interaction in humans, the clinical impact of the diclofenac and indometacin findings is probably minor. Similarly, while the modestly increased exposure to oxyphenbutazone with piperine cannot be directly extrapolated to humans, increased levels of oxyphenbutazone of this magnitude are unlikely to be of much clinical relevance.

Pepper + Oxytetracycline

The interaction between long pepper and oxytetracycline is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in hens, giving long pepper, equivalent to piperine 15 mg/kg, for 7 days, increased the AUC of a single 10-mg/kg oral dose of oxytetracycline given on day 8 by 27%. The elimination half-life was also increased by 29%. The rate of absorption of oxytetracycline was not affected by the pepper. Note that oxytetracycline levels were determined by microbial assay.

Mechanism

The authors of the study attributed the increased bioavailability to inhibition of microsomal metabolising enzymes by piperine in the long pepper.

Importance and management

This animal study provides some evidence that pepper might increase exposure to oxytetracycline. While it is not possible to directly apply these data to the clinical situation, the level of increases seen would not be expected to be clinically important.

Pepper + Phenytoin

Piperine appears to increase the maximum levels and AUC of phenytoin, although the effect may be less in patients receiving long-term phenytoin.

Clinical evidence

Pepper or its active alkaloid piperine have been reported to enhance the oral bioavailability of phenytoin in three clinical studies. In one crossover study, 6 healthy subjects received a single 300-mg dose of phenytoin 30 minutes after a soup with or without black pepper, 1 g per 200 mL. The presence of pepper increased the AUC0-48, AUC0-∞ and maximum plasma concentration of phenytoin by 49%, 133% and 13%, respectively, and the elimination half-life was increased from 22.48 to 49.71 hours. The pepper was added to the soup after preparation, and the piperine content of the soup was analysed and found to be 44 mg per 200 mL.

In another crossover study, 5 healthy subjects received a single 300-mg dose of phenytoin orally alone, or after pretreatment with piperine 20 mg daily for 7 days. Piperine increased the AUC and maximum plasma level of phenytoin by 50% and 27%, respectively. The rate of absorption of phenytoin was higher when given after piperine.

In a study in patients with epilepsy taking phenytoin 150 mg twice daily (10 patients) or 200 mg twice daily (10 patients), there was a minor increase in the AUC and maximum plasma concentrations of phenytoin when they were given a single 20-mg dose of piperine with their morning dose of phenytoin. The increase in AUC and maximum plasma concentrations of phenytoin were about 9% in the 150-mg phenytoin group, and 17% and 22%, respectively, in the 200-mg phenytoin group, and the elimination half-life was unchanged.

Experimental evidence

A study in mice found that the rate and extent of absorption of a single 10-mg oral dose of phenytoin were increased by the concurrent administration of oral piperine 0.6 mg, and the rate of elimination was reduced. Similarly oral piperine reduced the rate of elimination of phenytoin after an intravenous dose.

Mechanism

The increase in bioavailability of phenytoin caused by piperine may be the result of increased gastrointestinal absorption and decreased elimination. The effects of piperine in patients already taking phenytoin were far less marked than those in the healthy subjects given single doses of phenytoin. This might be because a single dose of piperine was given simultaneously with the phenytoin in the study in patients, rather than prior to the phenytoin. Alternatively, it could be that, after long-term use of phenytoin, piperine has little effect on the elimination of phenytoin.

Importance and management

The increases in AUC of single-dose phenytoin in the studies in healthy subjects with pretreatment with pepper or piperine would be considered clinically relevant. However, more minor, clinically irrelevant increases were seen when a single dose of piperine was given simultaneously with a dose of phenytoin in patients on established phenytoin therapy. It is unclear if, had the administration schedules in the healthy subject studies been used in the patient study, a greater effect might have been seen. However, the widespread use of pepper in cooking and Ayurvedic medicine, and the lack of any reports of phenytoin toxicity, provide some reassurance that an interaction is unlikely. Nevertheless, bear the possibility of an interaction in mind if a patient who starts taking piperine-containing supplements presents with unexpectedly high phenytoin levels.

Pepper + Propranolol

Piperine pretreatment increased the AUC of a single dose of propranolol by twofold in a study in healthy subjects.

Clinical evidence

In a study in 6 healthy subjects who received a single 40-mg dose of propranolol alone, and after taking piperine 20 mg daily for 7 days, the bioavailability of propranolol was significantly increased, with a twofold increase in both the AUC and maximum plasma concentration. However, the rate of elimination of propranolol was unaffected by piperine.

Experimental evidence

No relevant data found.

Mechanism

Piperine is known to increase the absorption of some substances from the gastrointestinal tract, but the exact mechanism is unclear.

Importance and management

The effect of piperine on propranolol in this study was fairly large, but increases of this level are not usually considered clinically relevant with drugs such as propranolol that have marked variation in levels between individuals, and are titrated to effect. Also, this dose of piperine is easily achievable by the consumption of black pepper in the diet, and there do not appear to be any reports of interactions. Moreover, because it involved only a single dose of propranolol, its findings might not be replicated in the clinical situation. Nevertheless, bear the possibility of an interaction in mind if a patient who starts taking piperine-containing supplements presents with an unexpected increase in adverse effects of propranolol, such as hypotension or bradycardia.

Pepper + Rifampicin (Rifampin)

Piperine increased the AUC of rifampicin, but a small dose of Trikatu had no effect.

Clinical evidence

In a study, 14 patients with pulmonary tuberculosis were given a single 450-mg dose of rifampicin alone, repeated 5 days later with a 50-mg dose of piperine, extracted from Piper nigrum. The maximum plasma level and AUC of rifampicin were significantly increased by piperine, by 29% and 70%, respectively.

In contrast, in a single-dose study in 6 healthy subjects, when rifampicin 450 mg was given with a small dose of Trikatu extract 50 mg the maximum level was slightly reduced by 18% and the time to maximum level was slightly delayed, but these changes were not statistically significant. Trikatu is an Ayurvedic medicine which contains ginger, black pepper and long pepper in a 1:1:1 ratio. Although the preparation used was not analysed for piperine content, it is estimated that this could have been about 1 mg in the 50 mg of Trikatu, based on findings of other studies.

Experimental evidence

In a placebo-controlled study in rabbits, a single dose of Trikatu 500mg/kg was given with rifampicin 24mg/kg. The rabbits were then given the same dose of Trikatu once daily for 7 days, with a single 24-mg/kg dose of rifampicin on day 7. In the single-dose study, the maximum plasma concentration of rifampicin was reduced by just 15%. The AUC was also reduced to a similar extent, but this was not statistically significant. In the multiple-dose study, Trikatu did not significantly alter the pharmacokinetics of rifampicin. The quantity of piperine in the Trikatu was estimated to be 1 mg per 50mg.

Mechanism

Unknown.

Importance and management

These are conflicting results, which may be caused, in part, by the use of markedly different doses of piperine, as well as the use of the plant extract and pure piperine. The findings are difficult to interpret, but the widespread use of pepper in cooking and lack of reports of interactions with rifampicin give some reassurance that any interaction is unlikely to be clinically important.

Pepper + Theophylline

Piperine almost doubled the AUC of a single dose of theophylline.

Clinical evidence

In a study in 6 healthy subjects who received a single 150-mg dose of theophylline alone, and after taking piperine 20 mg daily for 7 days, the bioavailability of theophylline was significantly increased, with an increase in the AUC and maximum plasma concentration of 96% and 61%, respectively. The elimination half-life of theophylline was extended from about 6.6 to 10.8 hours. Although not specifically stated, it is assumed that this study used a standard-release theophylline preparation.

Experimental evidence

No relevant data found.

Mechanism

Piperine is known to increase the absorption of some substances from the gastrointestinal tract, but the exact mechanism is unclear. However, theophylline already has high oral bioavailability. The finding of an increased elimination half-life suggests a mechanism of reduced metabolism or clearance. Pipeline is known to inhibit some of the cytochrome P450 isoenzymes, although there do not appear to be any data specifically on CYP1A2, which is mainly involved in the metabolism of theophylline.

Importance and management

This study appears to show a marked increase in exposure to single-dose theophylline when given with a dose of piperine that might easily be achieved with pipeline-containing supplements or even from consuming black pepper. How the findings relate to the use of multiple-dose theophylline or sustained-release formulations is also unknown. The widespread use of pepper in cooking and lack of reports of interactions with theophylline gives some reassurance that any interaction is unlikely to be clinically important. Nevertheless, until more it known, it would be prudent to be cautious with the use of piperine-containing supplements in patients taking theophylline.

Pepper + Thyroid and Antithyroid drugs

The interaction between piperine and thyroid drugs, such as levothyroxine, or antithyroid drugs, such as carbimazole, is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

Piperine was evaluated for its thyroid-hormone and glucose-regulatory effects in a study in mice. Oral piperine 2.5mg/kg daily for 15 days lowered the serum levels of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) as well as glucose concentrations. The decreases were comparable to that of the antithyroid drug, propylthiouracil. A 10-fold lower dose of piperine (0.25 mg/kg) had little effects.

Mechanism

Not known. Piperine appears to have antithyroid activity.

Importance and management

This preclinical study provides some evidence that piperine, the main active constituent of pepper, might have antithyroid effects. Theoretically this may have additive effects with other antithyroid drugs, such as propylthiouracil or carbimazole, and could antagonise the effects of levothyroxine. It is not possible to directly apply these data to the clinical situation, and how the doses used relate to usual human consumption of pepper or the dose of piperine in supplements is unclear. Note that there appears to be no evidence of pepper or piperine being a problem in patients with thyroid disorders. This study does not provide sufficient evidence to recommend caution in patients requiring thyroid supplementation. Bear in mind the possibility of an interaction in a patient requiring an increase in levothyroxine dose after starting piperine-containing supplements.

Pepper + Verapamil

The interaction between piperine and verapamil is based on experimental evidence only.

Evidence, mechanism, importance and management

In an in vitro study, the CYP3A4-mediated metabolism of verapamil to norverapamil was inhibited by the presence of piperine, but the CYP2C-mediated metabolism of verapamil was not significantly altered by piperine. It is difficult to apply this finding to human intake of pepper. However, a clinical study is needed to assess whether ingestion of pepper or piperine-containing supplements actually alters verapamil levels. Until more is known, bear this finding in mind in the event of unexpected outcomes in patients taking verapamil and piperine-containing supplements.